Erythrocytes in human blood are infected by malaria parasite Plasmodium falciparum, resulting in all the symptoms and pathologies of the disease. Conservative estimates predict 2-300 million people are afflicted with malaria and over a million children die from the infection each year. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of host and parasite interactions provides one approach to new drug and vaccine development. Plasmodium falciparum causes the most virulent form of human malaria. A striking feature of P.falciparum is its development in a vacuole when it infects the erythrocyte. This host cell is non-endocytic and does not invaginate its plasma membrane. Yet P. falciparum induces both membrane invagination and vacuole formation in these cells. Thus it must induce endocytic mechanisms to take up solutes and macromolecules. The long term aim of this proposal is to identify and characterize the mechanisms by which endocytic vacuoles in erythrocytes can be induced by malaria parasites. The studies will contribute to our understanding of the basic biology of the erythrocyte and parasite, and thereby contribute to human health. Molecular, genetic tools using transfection, genomics combined with high resolution imaging techniques and biochemical subcellular fractionation assays will be used to identify and purify erythrocyte membrane components that are recruited into the vacuole and evauate their interactions with specific lipids and protein components of both host and parasite origin. The consequence of ablation parasite gene products or expression of transdominant forms of mutant parasite genes on erythrocyte vacuole formation, expression of antigens on the erythrocyte surface, drug and toxin uptake and parasite growth will be evaluated in vitro cultures. These studies maybe important for understanding mechanisms of chemo and immunprophylaxis directed against erythrocyte membrane defects as well infection by a major human pathogen. The maintenance of human erythrocyte function in circulation, clearance of older red cells and the production of new ones must all be carefully coordinated to optimize tissue oxygen delivery. This requires understanding of erythrocyte membrane function. We utilize malaria parasites as a probe to study erythrocyte membrane function and their modulation by parasite pathogenic processes. Our studies are aimed at understanding how to better target drugs and other therapies to erythrocyte membrane defects as well as infection of these cells by a major human pathogen.